Ribosomal biogenesis induction by high glucose requires activation of upstream binding factor in kidney glomerular epithelial cells

Meenalakshmi M. Mariappan, Kristin D'Silva, Myung Ja Lee, Kavithalakshmi Sataranatarajan, Jeffrey L. Barnes, Goutam Ghosh Choudhury, Balakuntalam S. Kasinath

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Diabetes promotes protein synthesis to induce kidney hypertrophy and increase renal matrix proteins. Increased capacity for mRNA translation by way of ribosomal biogenesis facilitates sustained stimulation of protein synthesis. We tested the hypothesis that high glucose induces ribosomal biogenesis as indicated by an increase in rRNA synthesis in the setting of augmented protein synthesis. High glucose (30 mM) increased global protein synthesis, expression of matrix proteins, laminin γ1 and fibronectin, and rDNA transcription in glomerular epithelial cells (GECs) compared with 5 mM glucose. High glucose induced Ser388 phosphorylation of upstream binding factor (UBF), an rDNA transcription factor, along with increased phosphorylation of Erk and p70S6 kinase. Inactivation of Erk and p70S6 kinase either by their respective chemical inhibitors or by expression of their inactive mutant constructs blocked high-glucose-induced UBF phosphorylation. High glucose reduced nuclear content of p19ARF and promoted dissolution of inactive UBF-p19ARF complex. High glucose also promoted association of UBF with RPA194, a subunit of RNA polymerase I. Inhibition of Erk, p70S6 kinase, and UBF1 by transfecting GECs with their respective inactive mutants abolished laminin γ1 synthesis, protein synthesis, and rDNA transcription. Renal cortex from type 1 diabetic rats and type 2 diabetic db/db mice showed increased phosphorylation of UBF, Erk, and p70S6 kinase coinciding with renal hypertrophy and onset of matrix accumulation. Our data suggest that augmented ribosome biogenesis occurs in an UBF-dependent manner during increased protein synthesis induced by high glucose in the GECs that correlates with UBF activation and renal hypertrophy in rodents with type 1 and type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)F219-F230
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Diabetic kidney disease
  • Hypertrophy
  • Mammalian target of rapamycin
  • Polymerase I
  • Ribonucleic acid
  • Ribosomal deoxyribonucleic acid transcription

ASJC Scopus subject areas

  • Physiology
  • Urology

Fingerprint Dive into the research topics of 'Ribosomal biogenesis induction by high glucose requires activation of upstream binding factor in kidney glomerular epithelial cells'. Together they form a unique fingerprint.

Cite this